Fresh hope in hunt for malaria vaccine

“A group of children… naturally immune to malaria are helping scientists to develop a new vaccine,” BBC News reports.

Researchers hope the children could be key to developing a viable vaccine for malaria, which kills more than half a million people every year, many of them children.

Researchers are attempting to develop a new type of malaria vaccine based on proteins found in the blood of children who have a natural resistance to the disease.

The prototype vaccine has been found to partially reduce malaria infection in mice.

The vaccine stops the malaria parasite from leaving red blood cells so it is trapped inside and cannot cause further infection and damage.

A word of caution though; some candidate vaccines in the past have shown promise in animals but turned out not to work in people. However, encouragingly, the vaccine appeared to mimic the natural resistance to malaria infection found in some children and adolescents living in malaria endemic regions of Africa.

The next steps for the research, outlined by the study authors in The Independent, include “active vaccination trial in monkeys, followed by phase-one trials in humans. We’d like to roll this out as quickly as we can”.

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Where did the story come from?

The study was led by researchers from the US Center for International Health Research, Rhode Island Hospital in collaboration with other US universities and institutions. It was funded by grants from the US National Institutes of Health, the Bill & Melinda Gates Foundation, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

The UK media’s reporting was generally balanced and accurate. It stressed the fact that while the research was promising, there were still many developmental hurdles (trials in monkeys and in humans) to pass through before the vaccine would be fully developed and available for use.

What kind of research was this?

This was a laboratory study in mice looking for new targets in the malaria infection cycle on which to develop a new vaccine.

Malaria is a serious infectious disease spread by mosquitos that can cause death if not diagnosed and treated quickly. It is caused by plasmodia parasites, of which five types are known to cause malaria in humans. Once a person is bitten by a plasmodia carrying mosquito, the parasite enters the bloodstream where it replicates and spreads. Around seven to 18 days after infection symptoms appear including fever, headaches, vomiting, muscle pains and others.

The aim of a vaccine is to interrupt the malaria infection process which has many stages and potential target points. Many attempts at a malaria vaccine have been made already but the researchers indicate around 60% of these focus on just four main targets in the malaria infection cycle as the basis of how they work. They say that new targets are needed and new vaccines must be developed to take advantage of these targets.

What did the research involve?

The research had four phases.

Phase one

The first aimed to identify new vaccine targets using a group of young Tanzanian children who showed natural resistance to malaria infection. The researchers performed blood tests and DNA analysis on 12 resistant and 11 susceptible two year old children to look for clues as to why some were naturally more resilient to the infection than others. This process identified the plasmodium falciparum schizont egress antigen-1 (PfSEA-1) protein. The PfSEA-1 protein was involved in enabling the malaria parasite to exit infected red blood cells to spread and infect other cells.

Phase two

Having identified the new target, the researchers developed a prototype vaccine designed to disrupt the PfSEA-1 protein, trapping the parasite in the blood cells. They gave the prototype vaccine to mice before infecting them with a lethal dose of malaria parasite. The vaccine reduced the amount of parasite measured in the blood (how infected they were), and delayed the death of the mice from malaria.

Phase three

The researchers tested whether any of the Tanzanian children (453 tested, aged between 1.5 and 3.5 years) had an immune response to the PfSEA-1 protein. This would indicate whether a natural version of the vaccine, targeting the PfSEA-1 protein, was in their bodies and responsible for some of their natural resistance to malaria.

Phase four

The final stage aimed to test for the presence of an immune response to the PfSEA-1 protein in a completely separate group of people – a group of 138 male Kenyans aged between 12 and 35 living in villages with endemic malaria. They were looking to see if natural immunity to the PfSEA-1 protein in this group was linked to more favourable malaria infection outcomes such as lower levels of parasite in the body.

What were the basic results?

The main results of the research were:

The identification of a new vaccine target – the PfSEA-1 protein.

The development of a vaccine that disrupted the function of this protein.

Testing the vaccine in mice revealed significantly less malaria parasite infection in the blood in those given the vaccine. Infected vaccinated mice also lived 80% longer before eventual death than those infected but not given the vaccine. Both measures indicated the vaccine was partially protective against malaria.

Natural immune response to the PfSEA-1 protein was found in 6% of the Tanzanian children tested and this significantly decreased their risk of developing severe malaria. Natural immune responses to other existing malaria vaccines were not related to risk of severe malaria.

In an unrelated adolescent Kenyan group, 77 of 138 adolescents had immunity related to the PfSEA-1 protein and this gave them 50% lower densities of parasite in their bodies compared with people with no detectable immunity to the protein. This analysis adjusted for age, week of follow-up, exposure to Anopheles mosquitoes, and blood haemoglobin phenotype.

How did the researchers interpret the results?

The researchers concluded “our data validate our field-to-lab-to -field-based strategy for the rational identification of vaccine candidates and support PfSEA-1 as a candidate for pediatric falciparum malaria. By blocking schizont egress [the infection being released from the red blood cell], PfSEA-1 may synergize with other vaccines targeting hepatocyte and RBC [red blood cell] invasion”.

In other words, although this vaccine appears to have a partial response, it might be highly effective if it was combined with additional vaccines that had other targets in the lifecycle of the plasmodia infection.

Conclusion

Using a combination of laboratory protein experiments, mouse infection studies, and human susceptibility cohorts, this research developed a new prototype vaccine targeting the PfSEA-1 protein.

The vaccine appeared to mimic the natural resistance to malaria infection found in some children and adolescents living in malaria endemic regions of Tanzania and Kenya.

It is important to note that the vaccine was not 100% effective but, if developed successfully, it may still be useful if used in combination with other vaccines.

Though this looks hopeful, some candidate vaccines in the past have shown promise in animals such as mice and monkeys, but turned out not to work in humans.

This is a risk for this new vaccine as it hasn’t been tested in humans yet. There also may be side effects that mean the vaccine is not suitable for humans.

However, the new vaccine comes from a protein that has been shown to give naturally higher levels of malaria resistance in children. So this gives it a tentatively higher prospect of working in humans.

The likely next steps for the research were outlined by the study authors in the Independent, “our next destination is an active vaccination trial in monkeys, followed by phase-one trials in humans. We’d like to roll this out as quickly as we can”. This will provide the next stage of proof into whether it will work in high order mammals and humans.

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Malaria is a tropical disease. It is spread by mosquitoes infected with malaria parasites. In this video, an expert explains how malaria attacks different areas of the body, and what you can do to avoid getting infected.